Exposure to Anesthesia in Young Increases Risk for ADHD

Author: Michael Vlessides

Anesthesiology News

Children exposed to anesthesia for a single, minor surgical procedure before 5 years of age are more likely to take medications later for attention-deficit/hyperactivity disorder (ADHD), compared with unexposed children.

The findings from this study are consistent with earlier ones that demonstrated increased risk for ADHD and behavioral deficits in children with early anesthesia exposure.

“But with all these studies, there have been some signals that there may be an increased risk of behavioral and executive function deficits in children who have been exposed,” he said. “So the goal of this study was to try to determine whether a single exposure to surgery and anesthesia at an early age was associated with an increased risk of ADHD medication use, because behavior and executive function deficits are both associated with ADHD.”

The investigators used Medicaid claims from 1999 to 2010 from Texas and New York to generate a longitudinal birth cohort of approximately 2 million children. From among these records, they used International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes to identify those who had a single exposure to one of four surgical procedures with anesthesia—pyloromyotomy, inguinal hernia repair, circumcision outside the perinatal period, and tonsillectomy/adenoidectomy—before age 5.

Each exposed child was then matched with five unexposed children based on age at exposure. Propensity scores were calculated using sociodemographic variables, clinical covariates and year of exposure.

“Our primary outcome of interest was persistent ADHD medication use, which we defined as the presence of pharmacy claims for at least two filled prescriptions for greater than 30 days at any time after exposure to anesthesia,” Dr. Ing told Anesthesiology News.

The analysis identified 42,687 children who were exposed to anesthesia during one of the benchmark procedures. These children were matched with 213,435 controls.

In terms of cumulative incidence, the analysis revealed that regardless of the child’s age at exposure, those who were exposed were at 37% increased risk for persistent ADHD medication use thereafter. These results were fairly consistent when classified according to age of exposure:

• no more than 1 year: 1.22 hazard ratio (HR);
• greater than 1 year to no more than 2 years: 1.46 HR;
• greater than 2 years to no more than 3 years: 1.44 HR;
• greater than 3 years to no more than 4 years: 1.47 HR; and
• greater than 4 years to no more than 5 years: 1.24 HR.

The researchers also examined each procedure individually, finding that each was associated with an increased risk for persistent ADHD medication use: pyloromyotomy (HR, 1.35 for all ages combined; 95% CI, 1.08-1.68); inguinal hernia repair (HR, 1.12; 95% CI, 0.95-1.31); circumcision (HR, 1.23; 95% CI, 1.10-1.38), and tonsillectomy/adenoidectomy (HR, 1.48; 95% CI, 1.39-1.58).

As Dr. Ing reported at the 2019 annual meeting of the International Anesthesia Research Society (abstract F151), he and his colleagues then performed a series of sensitivity analyses to determine the robustness of the findings. The first of these saw the researchers exclude patients undergoing tonsillectomy/adenoidectomy from the analysis.

“We did this because [tonsillectomy/adenoidectomy] is associated with obstructive sleep apnea, which itself is associated with ADHD or ADHD-like symptoms,” Dr. Ing explained. “So that could be the issue with those children.”

After excluding these children, the HR was still 1.21 for all ages combined in children exposed to the other three procedures (95% CI, 1.12-1.32).

The researchers then redefined their outcome. “Maybe persistent ADHD medication use should be more than two filled prescriptions after exposure,” he said. “So we reclassified the outcome as either at least three prescriptions or at least four prescriptions, to see how that would impact the association.”

When the definitions were made stricter, the associations actually got stronger. Indeed, when redefining the outcome to be at least three prescriptions, the cumulative HR was 1.38 (95% CI, 1.31-1.46); the HR for at least four prescriptions was 1.41 (95% CI, 1.33-1.49).

The third sensitivity analysis evaluated the use of nonpsychotropic and other psychotropic medications.

“Maybe children who undergo surgery and anesthesia are simply sicker,” Dr. Ing explained. “And despite our best efforts with matching, they’re just seeing the doctor more and taking all types of medications at a higher rate than the matched, unexposed children.”

This analysis found that children exposed to anesthesia before 5 years of age did, indeed, demonstrate increased use of agents such as amoxicillin (HR, 1.06; 95% CI, 1.04-1.07), azithromycin (HR, 1.10; 95% CI, 1.08-1.12), and diphenhydramine (HR, 1.08; 95% CI, 1.05-1.11).

“So the way we interpret that is that our matching was not as perfect as expected and there’s unmeasured confounding,” Dr. Ing explained. “Nevertheless, ADHD medication use was still disproportionately higher than these common medications, which makes us believe that perhaps unmeasured confounding isn’t the only thing going on.”

Nevertheless, the children with greater dependence on ADHD medications also had greater use of psychotropic medications, including sedatives and anxiolytics (HR, 1.37; 95% CI, 1.25-1.51), antidepressants (HR, 1.40; 95% CI, 1.25-1.58), antipsychotics (HR, 1.31; 95% CI, 1.20-1.44), and mood stabilizers (HR, 1.24; 95% CI, 1.11-1.40).

“There’s an increased risk of using these drugs as well, one similar to that of the ADHD medication use, which is still disproportionately higher than use of nonpsychotropic medications. So when we’re saying that maybe these children need medications at a higher rate, it’s not all medications; they need these specific medications at a higher rate than other medications.”

Despite the findings, the researchers were quick to point out that they may have little impact on clinical practice at this point. “It’s one thing if it’s a study of fatty foods and you tell the children not to eat fatty foods,” Dr. Ing said. “But you can’t tell someone to not undergo a [tonsillectomy/adenoidectomy], for example, because they need that for a medical reason.”

Real Versus Theoretical Risks

Andrew Davidson, MD, MBBS, the head of anesthesia research at the Royal Children’s Hospital, in Melbourne, Australia, said the current study builds on previous research by the investigators (Anesth Analg 2017;125[6]:1988-1998) and “provides increased richness to the whole theory.”

Yet as Dr. Davidson discussed, findings such as these may conflict with the primary issue before anesthesiologists. “My ultimate concern is looking after the child in front of us and making sure that we can support them when they’re having surgery,” he said.

“That’s a common theme that comes through the whole neurotoxicity argument,” he added: “Don’t create a real risk by treating a theoretical risk. And delaying surgery is a real risk for surgery, whereas neurotoxicity is still a fairly theoretical risk.”

Nevertheless, Dr. Davidson recognized the need for more research in the area. “That said, it doesn’t reduce the need to better understand what’s going on as far as the long-term association between surgery, anesthesia and some aspects of neurodevelopmental outcome. There’s sufficient biological evidence to show that it’s biologically plausible, and there are sufficient cohort studies to show that there’s some association. So it’s like saying be alert, but not alarmed.”